Journal Article

Polymorphisms in DNA repair genes in the molecular pathogenesis of esophageal (Barrett) adenocarcinoma

Alan G. Casson, Zuoyu Zheng, Susan C. Evans, Paul J. Veugelers, Geoffrey A. Porter and Duane L. Guernsey

in Carcinogenesis

Volume 26, issue 9, pages 1536-1541
Published in print September 2005 | ISSN: 0143-3334
Published online May 2005 | e-ISSN: 1460-2180 | DOI:
Polymorphisms in DNA repair genes in the molecular pathogenesis of esophageal (Barrett) adenocarcinoma

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To test the hypothesis that aberrations of DNA repair contribute to susceptibility for the progression of gastroesophageal reflux disease (GERD) into Barrett esophagus (BE) and esophageal adenocarcinoma (EADC), we studied the frequency of polymorphisms of selected DNA repair genes in patients with GERD (n = 126), BE (n = 125) and EADC (n = 56) enrolled in a 2-year prospective case–control study. Controls comprised 95 strictly asymptomatic healthy individuals. Using genomic DNA extracted from blood samples, we identified wild-type and polymorphic variants of XPD (Arg156Arg and Lys751Gln), XRCC1 (Arg194Trp and Arg399Gln) and XRCC3 (Thr241Met), and the poly (AT) insertion/deletion of XPC (PAT). Allelic frequencies were compared between cases and controls using logistic regression to calculate age, gender, smoking and alcohol-adjusted odds ratios (OR) and 95% confidence intervals (CI). Patients with EADC demonstrated a significantly higher frequency of the XPC PAT homozygous variant genotype compared with asymptomatic controls (OR = 3.82; 95% CI = 1.05–13.93). Significantly reduced frequencies were seen for the XPD Lys751Gln homozygous variant genotype in patients with EADC (OR = 0.24; 95% CI = 0.07–0.88), and for the XRCC1 Arg399Gln homozygous variant genotype in patients with BE (OR = 0.38; 95% CI = 0.12–0.64) and GERD (OR = 0.29; 95% CI = 0.12–0.66). We conclude that the malignant phenotype probably results from a summation of polymorphic nucleotide excision repair genes showing opposing effects (an increased risk of XPC versus a protective effect of XPD). The protective effect of the homozygous variant of XRCC1 Arg399Gln for GERD and BE suggests that base excision repair alterations may occur early in progression to EADC, likely in response to GERD-induced endogenous oxidative or inflammatory DNA damage. As GERD and BE are highly prevalent in the general population, this protective effect may well explain why only a fraction of individuals with GERD and BE progress into invasive EADC.

Keywords: BE, Barrett esophagus; BER, base excision repair; CI, confidence interval; EADC, esophageal adenocarcinoma; GERD, gastroesophageal reflux disease; MMR, mismatch repair; MSI, microsatellite instability; NER, nucleotide excision repair; OR, odds ratio; PCR, polymerase chain reaction; PAT, poly(AT); XPG genes, xeroderma pigmentosum group genes; XRCC genes, X-ray repair cross-complementing genes.

Journal Article.  5256 words. 

Subjects: Clinical Cytogenetics and Molecular Genetics

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